The goal of this program project are to mount an interdisciplinary and highly collaborative program to study the p53 tumor suppressor protein and to translate findings into more rational treatment of cancer patients. This will require combining findings from structural, biochemical and molecular approaches with animal models and analysis of human tumors. To understand proteolysis of p53 N. Pavletich will perform X-ray crystallography to determine the structure of a complex of p53, E6 and E6AP proteins. He will also work with A. Levine and to perform structural studies on Mdm2 with RNA, and with C. Prives to study the interaction of p53 with upstream DNA damage-responsive protein kinases. C. Prives will study the roles and properties of protein kinases which phosphorylate p53 after stress signals and will also examine the properties of of p53 family members p63 and p73. Prives will collaborative with Levine to study phosphorylation of Mdm2, and to compare downstream responses of cells to p53 family members. A. Levine will examine the impact of genetic background on the downstream response of p53 induction in inbred strains of mice, and will also study nucleo-cytoplasmic shutting by Mdm2. In addition, collaborative studies Leine will work with Cordon-Cardo to study the impact of genetic background on human cancer patients response to cancer therapy. S. Lowe will exploit a mouse E:-Myc lymphoma mouse model to evaluate the p53 response and to identify the genetic determinants in mice which would affect their disease and response to cancer therapy. Lowe will collaborate with Prives to study the role of oncogenes in signaling to p53 and with Cordon-Cardo will apply findings of genes known to affect p53 response in animals to evaluation of their status in human tumors. Finally, Cordon-Cardo will translate findings from these studies in order to development molecular markers with predictive value with the eventual goal of tailoring treatment and management of individual cancer patients. Thus the co-PIs of this program will work together to accumulate a broad spectrum of new discoveries about p53 and to exploit their findings for clinical purposes.